Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-02-16
2002-07-23
Spivack, Phyllis G. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06423739
ABSTRACT:
FIELD OF THE INVENTION
The present invention concerns the use of a cyclic gamma-aminobutyric acid (GABA) derivative, namely N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl) acetamide, as a drug for combating neurodegeneration, particularly after a stroke, for improving the Activities of Daily Living (ADL) after a stroke or for recovering, or at least for improving the recovery of, a post-stroke patient.
BACKGROUND OF THE INVENTION
It is known that a way to assess physical impairment in post-stroke patients, besides the neurological motor and sensory examination, is to quantitate deficits in the performance of daily activity (ADL) according to assessment scales, such as the John Hopkins Functioning Inventory (JHFI) or analogous ones, which determine the patients' ability to accomplish normal operations, in particular keeping the sitting or standing position, walking, washing, dressing, undressing, eating meals, bathing and using the lavatory. The assessment, the impairment, as well as and the need of recovery of ADL after stroke are illustrated by Robert G. Robinson “The Clinical Neuropsychiatry of Stroke”, 1998, Cambridge University Press, pages 143, 222-225 and 292-293.
Depression is the main disorder associated with stroke and there is a correlation between the severity of depression and the severity of impairment in ADL. For the improvement in the impairment of ADL and, as a consequence, for the improvement in the recovery from stroke, patients are mainly treated with antidepressant drugs and, according to the above cited reference, there are no documented pharmacological treatments, apart from said antidepressants treatments, which improve physical or cognitive recovery from completed stroke. Supra Robinson, p. 293.
Cyclic GABA derivatives, more particularly 2-oxopyrrolidine derivatives, are compounds extensively used in pharmaceutical compositions for the improvement of memory and attention and are known as mnemotonic or nootropic agents. Typical drugs of this class include 2-oxo-1-pyrrolidineacetamide (piracetam), 1-(4-methoxybenzoyl)-2-pyrrolidinone (aniracetam) and 4-hydroxy-2-oxo-1-pyrrolidineacetamide (oxiracetam).
DESCRIPTION OF THE ART
It is known (BE 883791-U.S. Pat. No. 4,341,790) that anilides of 2-oxo-1-pyrrolidineacetamide show central vasoactive and tranquilizing properties as well as the ability of regulating the metabolism and inhibiting thrombocyte agglutination. Thus, said compounds are deemed to be useful for the treatment of cerebro-ischaemic or atrophic diseases, brain irrigation disorders, brain atrophic crises as well as of brain aging processes. Among these anilides of 2-oxo-1-pyrrolidineacetamide, the 2,6-dimethylanilide, i.e., N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl)acetamide, known and hereinafter referred to as nefiracetam, represented by the formula (A)
has been reported to be effective in prolonging the survival time upon a decrease in blood oxygen level and in relieving failure of memory due to cerebropathy.
The literature extensively discloses (see for example E. Ohtomo et al., J Clin. Exp. Med., Suppl., 1994, 170/9, 777-816) the usefulness of nefiracetam in improving psychiatric disorders associated with cerebrovascular diseases such as stroke (cerebral infarction or cerebral hemorrhage), this activity being a consequence of the favorable action of nefiracetam on the cerebral irrigation, as suggested by BE 883791.
It is also known (K. Hirata et al., Brain Topography 1996, 8/3, 279-284) that nefiracetam acts as a cerebral metabolic enhancer in improving the mental function impairment in stroke patients, thus confirming the suggestion of BE 833791 which disclosed the metabolism-regulating properties of the compound. Hirata et al., however, conclude that the improvement of mental function tests was not significant.
Moreover, it is known (U.S. Pat. No. 5,886,023) that nefiracetam improves symptoms of cerebrovascular or Alzheimer's type dementia due to a decline in mental function.
All these documents indicate that the efficacy of nefiracetam in the symptomatic treatment of impaired mental function is due to its ability in improving the cerebral irrigation or to its metabolism-regulating properties. Psychiatric symptoms and cognitive impairment are frequently observed following stroke and negatively affect both the patient and the caregiver.
In the above-cited article of Ohtomo et al., the global results of a clinical study, conducted in two groups of patients to which nefiracetam and, respectively, placebo were administered after a stroke (cerebral infarction or celebral hemorrhage), showed that the compound improves the psychiatric symptoms but concluded that there was no significant difference between the two groups as far as the activities of daily living were concerned. Thus, according to these results nefiracetam appeared as inactive in improving the disturbances of the activities of daily living in post-stroke patients. A positive effect in this indication could suggest a curative use of a drug for the recovery from a stroke or, at least, for an improved recovery from stroke.
SUMMARY OF THE INVENTION
It has now surprisingly been found that, if nefiracetam is administered to a patient, suffering from the consequences of a stroke, early after the event or at the most within the first six months after the stroke, a significant improvement with regard to the global disturbances of the activities of the daily living is observed.
More particularly, it has been found that nefiracetam is able to induce an improvement in the recovery of post-stroke patients, provided that said nefiracetam is administered early after the event, at the most within the first six months after said event.
Moreover, it has surprisingly been found that nefiracetam possesses a remarkable neurotrophic activity which allows the regeneration of damaged neurons, thus being able to combat neurodegeneration, and that nefiracetam is particularly effective when the neurodegeneration is due to a stroke (cerebral infarction or cerebral hemorrhage).
The mechanism by which nefiracetam acts on the neurodegeneration, thus allowing, for example, a recovery or at least an improvement in the recovery from stroke, is unknown because nefiracetam does not possess known biochemical activities which are predictive and known for this action such as, for example an agonism for the 5HT1-A receptor or a positive modulation of AMPA-sensitive glutamate receptors (AMPA indicates &agr;-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid).
The neurotrophic, in particular anti-neurodegenerative property of nefiracetam, which was inferred on the basis of the clinical evidence of a significant improvement in the Activities of the Daily Living was confirmed by biochemical and animal tests.
DETAILED DESCRIPTION OF THE INVENTION
Thus, it is an object of the present invention to provide a method for improving the Activities of Daily Living (ADL) in a post-stroke patient which comprises administering to said patient an effective dose of nefiracetam, said administration being initiated within the first six months after the event.
In order to display the best activity, nefiracetam will be administered early or at least as soon as possible, advantageously within three month, preferably within one month after the stroke.
Nefiracetam can be administered in various manner to achieve the desired effect, for example for improving ADL in a post stroke patient or for the recovery of, or at least for improving the recovery of, a post-stroke patient. The compound can be administered alone or in the form of pharmaceutical compositions comprising a pharmacologically effective amount of nefiracetam as an active ingredient and a pharmaceutical acceptable carrier to the patient to be treated, preferably orally. The oral amount of nefiracetam administered will vary and can be any effective amount according to the physician's prescription. Normally, depending upon the patient and the mode of administration, the quantity of compound administered orally may vary over a wide range to provide from about 1 mg/kg
Otomo Eiichi
Takasu Yoshiyuki
Daiichi Pharmaceutical Co. Ltd.
Spivack Phyllis G.
Sughrue & Mion, PLLC
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